tbuckley/cabot-search huggingface dataset:
Abstract 11616: Obstructive Sleep Apnea Disrupts Endothelial Cellular Cholesterol Trafficking
Authors: Su Gao, Vikash Kumar Shah, Memet Emin, Audrey Chang, Sanja Jelic
Journal: Circulation (2022)

Introduction: Obstructive sleep apnea (OSA), a highly prevalent disorder, triples cardiovascular risk. Our previous studies showed that intermittent hypoxia (IH), the hallmark of OSA, triggers endothelial cell (EC) inflammation by reducing protection against complement activity, which is cholesterol-dependent. We assessed whether IH promotes accumulation of cellular cholesterol in ECs in OSA patients and investigated the underlying mechanisms. Methods: We used ECs collected from OSA patients and cultured human umbilical vein ECs (HUVECs) exposed to IH (alternating 30 min 21% O 2 for normoxia/30 min 2% O 2 for hypoxia for 8 h). Results: Levels of free, cellular cholesterol were increased and the presence of lipid droplets was reduced in ECs from OSA patients compared with OSA-free controls as well as in HUVECs exposed to IH compared with normoxia. Cholesterol uptake and synthesis were similar in normoxia and IH. In contrast, co-localization of free cholesterol and late endosome/lysosome (LE/LY) was increased in IH compared with normoxia, suggesting impaired trafficking of free cholesterol from LE/LY to endoplasmic reticulum (ER) in IH. Immunoglobulin binding protein (BiP), a marker of ER stress, was upregulated in ECs of OSA patients compared with controls. IH-induced ER stress reduced interaction between LE/LY-bound oxysterol binding protein-related protein-1L (ORP1L) and ER-bound VAMP-associated protein-B (VAPB), which is required for cholesterol trafficking from LE/LY to ER. After screening ER-associated degradation machinery components for potential binding to VAPB in IH, we identified Derlin1 as a ligand that binds increasingly to VAPB in IH thereby potentially reducing interaction between ORP1L and VAPB. In OSA patients, ORP1L-VAPB interaction was reduced whereas Derlin1-VAPB was increased and positive airway pressure, a standard therapy for OSA, reversed these changes. Conclusions: IH induces ER stress that disrupts cholesterol trafficking from LE/LY to ER leading to accumulation of free cholesterol in ECs, which underlies impaired endothelial protection against complement and endothelial inflammation that may increase cardiovascular risk in OSA.
Abstract 11506: Roles of Mechanical Overload and the Microtubule Network in Mediating T-Tubule Remodeling
Authors: Vasiliki Courelli, Keita Uchida, Alexia Vite, Benjamin Prosser, Kenneth B Margulies, Michael Ibrahim
Journal: Circulation (2022)

Background: Mechanical overload is an established contributor to the remodeling of T-tubules (TT) and associated dyssynchronous Ca 2+ release leading to abnormal excitation-contraction coupling in cardiomyopathies. We examined the induction of pathologic TT remodeling in isolated cardiomyocytes and the involvement of microtubules in this process. Methods: Normal adult rat ventricular myocytes (aRVMs) were cultured for 48hrs on MREs at either physiological (10kPa) or pathological (50kPa) stiffness. Variable in vitro load application was achieved using custom magnetorheologic elastomers (MREs) with tunable stiffness. Cells were stained with Di-8-ANEPPS and Fluo-4-AM and imaged using Airyscan confocal microscopy. Microtubule dependency was investigated by treating cells with 1μM nocodazole, a microtubule depolymerization agent.Structural changes in TT networks were quantified in terms of regularity, luminal dimensions, density, and directionality. Field stimulation of cells allowed for acquisition of [Ca 2+ ] i transients via line scans and subsequent analysis of key [Ca 2+ ] i transient parameters. Changes in protein expression were determined via Western blotting. Results: Compared to the physiological stiffness group, aRVMs subjected to pathologically increased stiffness exhibited decreased density and regularity of the TT system, and increased luminal dimension. Direction-specific density analysis showed that pathologically loaded cells have more longitudinal tubule elements and fewer transverse tubule elements. This remodeling was attenuated in aRVMs treated with nocodazole in terms of regularity, luminal diameter, and direction-specific density. The observed changes in both Ca 2+ handling parameters and key protein expression resembled those typical of the in vivo myopathic phenotype. Conclusion: The results suggest that load-induced TT remodeling occurs via a cardiomyocyte autonomous, microtubule-dependent mechanism.
Abstract 11721: Frailty Assessed by a Composite Assessment of Cognitive and Physical Frailty Predicts Long-Term Outcomes in Elderly Pre-Clinical Heart Failure Patients
Authors: Chen Meng, Hua Wang
Journal: Circulation (2022)

Introduction: We combined the Fried phenotype and the mini-mental state examination (MMSE) +clock drawing test (CDT) to assess frailty in elderly pre-clinical heart failure (HF) patients, and aimed to evaluated the prevalence and prognostic value of frailty assessed by this simple composite scoring system in this population. Methods: we conducted a single-center prospective observational cohort study in which enrolled inpatients≥ 65 years and followed up for 2 years. The primary outcomes were 2-year all-cause mortality or readmission. Multivariate Cox proportional hazard model was used to test the predictive validity. Results: Overall, 531 elderly pre-clinical HF inpatients were included in our study (mean age: 75.4±6.47 years, male: 230 [43.3%]). Among them, 11.7% (62/531) were assessed as cognitive impairment without physical frailty, 15.1% (80/531) were assessed as physical frailty without cognitive dysfunction and 13.0% (69/531) were assessed as cognitive frailty with physical frailty and cognitive impairment. The cognitive frailty individuals were older (P&lt;0.05), had shorter time of education (P&lt;0.001), higher level of N-terminal pro-B-type natriuretic peptide (P&lt;0.05), and were more likely to have comorbidities of peripheral arterial disease and the history of stroke (P&lt;0.05) and take ≥5 medications (P&lt;0.05). Physical frailty patients (P=0.019) and cognitive frailty patients (P=0.003) both had a higher incidence of mortality or readmission during 2-year follow-up and had a 1.50-fold (95%CI 1.04-2.18, P=0.03) and 1.84-fold (95%CI 1.19-2.83, P=0.01) higher risk of 2-year adverse events, respectively, after adjusting age, sex, marital status,education years,diabetes and the history of stroke. Conclusions: In conclusion, cognitive frailty is common in elderly pre-clinical HF patients. Adding cognitive impairment to physical frailty could predict all-cause mortality or readmission better in this population in the long term.
Abstract 11093: Spike Proteins Increase Endothelial Calcium via TRPV4
Authors: Hang Xing, Elizabeth O Harrington, Jun Feng
Journal: Circulation (2022)

Introduction: Endothelial dysfunction plays a central role in the pathogenesis of acute respiratory distress syndrome (ARDS) with COVID-19. Transient receptor potential vanilloid 4 (TRPV4), a cation channel ubiquitously expressed, can regulate inflammatory cytokines that play key roles in in acute lung injury/ARDS. However, it is unknown whether spike proteins can affect TRPV4 activity and related Ca 2+ signaling in pulmonary microvascular endothelial cells. Hypothesis: We hypothesized that spike protein causes activation of TRPV4 channels, resulting in increases in intracellular Ca 2+ , may lead to pulmonary endothelial dysfunction. Methods: Intracellular Ca 2+ concentrations in human lung microvascular endothelial cells (HLMECs) were measured by calcium imaging in the presence of SARS CoV-2 Spike protein S1, receptor-binding domain (RBD) of S1, or protein S2 with or without co-incubation of the selective TRPV4 antagonist (HC-067047). Results: The intracellular Ca 2+ concentration of HLMECs was significantly increased when incubated with S1 (1, 10nM) or S1 RBD (1, 10nM) for 12, 24, 48 hours, relative to control or S2 (p&lt;0.05, respectively, Fig. A, B). Co-incubation of HC-067047 (500nM) significantly attenuated Ca 2+ intracellular influx upon treatment with S1 (10nM, 24 hours, p&lt;0.05) or S1 RBD (10nM, 24 hours, p&lt;0.05) (Fig. C). TRPV4 sensitive current density was significantly increased when incubated with S1 (10nM) or S1 RBD (10nM) for 24 hours (p&lt;0.05 vs. control, respectively, Fig. D-G), whereas co-incubated with HC-067047 (500nM) significantly reversed the S1 (10nM, 24 hours, p&lt;0.05) or S1 RBD (10nM, 24 hours, p&lt;0.05) induced increases of TRPV4 sensitive current density (Fig. D-G). Conclusions: The of SARS CoV-2 Spike protein S1 and S1 RBD caused the activation of TRPV4 channels, resulting in increased intracellular Ca 2+ , may lead to pulmonary endothelial dysfunction.
Abstract 11469: Effects of Metformin and Donepezil on the Prevention of Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patient: A Randomized Controlled Trial
Authors: Nichanan Osataphan, Nattayaporn Apaijai, Arintaya Phrommintikul, KRIT LEEMASAWAT, Areewan Somwangprasert, Supanai Suksai, Siriporn Chattipakorn, Nipon Chattipakorn
Journal: Circulation (2022)

Introduction: Cardiotoxicity from doxorubicin (DOX) is the most concerning adverse event. Although data from preclinical studies showed that metformin and donepezil prevented myocardial injury and preserved mitochondrial function against DOX-induced cardiotoxicity, the beneficial effects of these drugs in clinical trial have not been established. Hypothesis: Oral administration with metformin or donepezil prior receiving DOX prevents DOX-induced cardiotoxicity in breast cancer patients. Methods: In this double-blind, placebo-controlled trial. We randomly assigned 111 female breast cancer patients to receive oral metformin 2000 mg (n=40), donepezil 10 mg (n=31), or placebo (n=40), once daily 1 day prior to DOX and continued during DOX treatment. Blood samples were obtained at baseline, after chemotherapy cycle 2 and 4. The primary outcome was the change of troponin-I (trop-I) from baseline. The secondary outcomes were the change in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline, and mitochondrial function in the peripheral blood mononuclear cells. Results: Baseline characteristics were similar between the groups, mean age was 51.93±10.45 years. The mean trop-I changed from baseline were 29.97±4.59 pg/ml in placebo group, 31.07±7.28 pg/ml in metformin group (p = 0.90 vs. placebo) and 30.97±5.07 pg/ml in donepezil group (p = 0.88 vs. placebo). The changes of NT-proBNP level and mitochondrial oxidative stress were comparable between placebo vs. metformin or donepezil groups. However, donepezil significantly decreased mitochondrial mass and mitochondrial maximal respiration after chemotherapy (Figure). Conclusion: In breast cancer patients undergoing chemotherapeutic treatment with DOX, metformin and donepezil did not prevent myocardial injury. Treatment with donepezil resulted in the decrease in mitochondrial mass and maximal respiration following chemotherapy that might caution its use in breast cancer.
Abstract 11055: Outcomes and Progression of Rasopathy-Associated Hypertrophic Cardiomyopathy
Authors: Michael Ho, Zachary Whitt, Joshua Meisner
Journal: Circulation (2022)

Background: RASopathy associated hypertrophic cardiomyopathy (HCM) is a frequent cause of pediatric onset HCM. RAS pathway inhibitors are a precision therapeutic option for RASopathy associated HCM. However, limited understanding of HCM progression and correlation with clinical outcomes currently restrict use to a compassionate basis, primarily in infancy. We hypothesize review of RASopathy associated HCM progression and outcomes will demonstrate burden of disease throughout childhood with the goal to identify high risk populations who may benefit from targeted therapies. Methods: A single-center retrospective review identified 59 patients with a diagnosis of HCM and a RASopathy. Echocardiographic, clinical, and molecular data were collected through chart review with echocardiographic measurements at set time points from neonate to young adult. Results: There was high overall mortality in our cohort (20.3%, n = 12). Cardiac arrest, transplant, or death was significantly higher in patients with heart failure in infancy (defined by need for diuretic use) (p&lt;0.001) (Fig 1A). There were no differences by syndrome or genotype. Pulmonary valve (PV) intervention was 16.9% (n = 10) and largely limited to infancy with median age 0.79 years (IQR 0.34-1.63) at first intervention. Incidence of atrial arrhythmias was 13.6% (n = 8) with median age of onset 0.44 years (IQR 0.35-0.88). Rates of septal myectomy were high (23.7%, n = 14). Myectomies, however, were not limited to infancy with median age at first myectomy 3.10 years (IQR 1.09-10.49) (Fig 1B). 21.4% (n = 3) required repeat myectomy. Conclusions: In contrast to previous research, our data suggest there is significant continued HCM growth outside of infancy as evidenced by high incidence of myectomy throughout childhood and young adulthood with frequent need for repeat myectomy. These suggest potential use of targeted therapies outside of infancy with further study needed to identify high-risk populations.
Abstract 115: Comparison Of Di-block Copolymer-based Cell Membrane Stabilizers To The Tri-block Poloxamer 188 In Protecting Coronary Artery Endothelial Cells Against Hypoxia-Reoxygenation Injury
Authors: Zhu Li, Mukesh K Gupta, Matthew B Barajas, Craig L Duvall, Matthias L Riess
Journal: Circulation (2022)

The triblock copolymer-based cell membrane stabilizer (CCMS) Poloxamer (P)188 consists of a central hydrophobic poly-propylene oxide (PPO) block that is flanked by two hydrophilic poly-ethylene oxide (PEO) blocks (PEO 75 -PPO 30 -PEO 75 ). It has been found to protect against various types of ischemia/reperfusion (IR) injury (e.g. stroke, traumatic brain injury, trauma, myocardial infarction) presumably by preserving membrane integrity and function. Modifications of its structure to di-block compounds (PEO-PPO) with a strongly hydrophobic (t) tert-butyl end-terminal were reported to yield even stronger protection. Recently, we demonstrated the critical importance of endothelial cells in mediating protection against IR injury of cardiomyocytes in a co-culture study. Here, we compared the protective effects of custom-made di-blocks (PEO 113 -PPO 10 t, PEO 226 -PPO 18 t and PEO 113 -PPO 20 t) at different concentrations (0 to 300 μM) on cell proliferation, lactate dehydrogenase (LDH) leakage and FM1-43 dye incorporation as markers of cell viability and membrane damage, respectively, to P188 in mouse coronary artery endothelial cells (MCAECs) when given upon the beginning of 2 hrs reoxygenation after 24 hrs hypoxia (HR) vs corresponding control normoxia (CN) conditions. Data are mean +/- standard deviation; statistics: ANOVA and SNK post-hoc testing, alpha = 0.05, # vs CN, * vs 0 mM. P188 as well as all three tested di-blocks significantly attenuated HR-induced cell damage dose-dependently; the figure shows the LDH data. This, for the first time, demonstrates that di-block compounds can protect MCAECs against HR injury as effective and even superior to P188. If translated clinically, di-block CCMS may become effective new compounds mitigating IR injury.
Abstract 11254: Impact of Transfer Status on Non-St Segment Elevation Myocardial Infarction Outcomes
Authors: Ahmad Gill, Omar Al-Taweel, Saba Al-Tarawneh, Mohammad Jaradat, DALIA HAWWASS, Chowdhury Ahsan
Journal: Circulation (2022)

Introduction: Patients who are transferred between acute care medical facilities are an overlooked population. In this study, we explore the in-hospital outcomes of patients with a non-ST segment elevation myocardial infarction (NSTEMI) who were transferred to an acute care hospital from another acute care center. Methods: We queried the National Inpatient Sample database (2016-2019) to identify patients admitted with a principal diagnosis of NSTEMI. We conducted propensity score matching using a greedy nearest neighbor 1:1 model. Multivariable logistic regression was used to compare mortality. Results: 131,948 patients met our inclusion criteria. Patients with a NSTEMI who were transferred from an acute care center had 1.20 times higher odds of suffering in-hospital mortality compared to regular hospital admissions (aOR 1.20, 95% CI: 1.13-1.28; p &lt; 0.001). When separated by race, acute care transfers had a higher mortality rate amongst White patients (3.5% vs 3.1%, p &lt; 0.001), but a decreased mortality rate in Black patients (3.5% vs 3.6%, p = 0.008, Figure 1). Acute care transfers were more likely to undergo percutaneous coronary intervention (35.9% vs 34.0%, p &lt; 0.001) and have intraoperative cardiac arrest (0.04% vs 0.01%, p &lt; 0.001, Table 1). Conclusions: Patients who were transferred to acute care hospitals from other acute care centers with a NSTEMI had higher odds of suffering in-hospital mortality compared to regular hospital admissions. Acute care transfers with a NSTEMI require additional medical support in the inpatient setting. Further studies should explore potential interventions to address these differences in outcomes.
Abstract 11336: Optimized Machine Learning Models by Identification of Candidate Predictors for 30-Day Readmission Risk Prediction Among Patients Hospitalized for Acute Myocardial Infarction
Authors: Likhita Sree Thiriveedi, Iben Ricket, Jeremiah R Brown
Journal: Circulation (2022)

Introduction: Acute myocardial infarction (AMI) is a leading cause of death in the US. More than 800,000 adults experience an AMI each year, and up to 20% of the patients are rehospitalized within 30 days. Predicting 30-day readmission accurately could help clinicians identify high-risk patients and tailor treatment accordingly. Hypothesis: The neural network will generate the best performing model for predicting 30-day readmissions following an AMI. Methods: The cohort included adults hospitalized with incident AMI (6,506) at Dartmouth Hitchcock Medical Center between 2011-2016. Patients who died before discharge (236) were excluded, leaving 6,270 patients. Our outcome was 30-day hospital readmissions. Candidate features were selected using an Extra Tree Classifier. Selected features included demographics and clinical characteristics. Multiple imputation using K-Nearest Neighbors was performed. Five machine learning models were implemented: logistic regression, LASSO, neural network, random forest, and XGBoost. Models were evaluated on a hold-out test-set, using AUROC. Results: Among the cohort, about 36% were female, the majority were white and non-Hispanic, and the 30-day readmission rate was 6.2%. Neural network was the best performing model with an AUROC of 0.80 (95% CI: 0.75, 0.84). However, the XGBoost and random forest models performed similarly with AUROCs of 0.80 (95% CI: 0.76, 0.85) and 0.79 (95% CI: 0.75, 0.84), respectively. The logistic regression and LASSO models performed poorly, with AUROCs below 0.5, respectively. Important predictor variables were major depression, race, and antidepressant at discharge. Conclusions: Neural network, random forest, and XGBoost models predicted 30-day readmission following an AMI with good performance. Across these models, depression was an important feature for predicting 30-day readmissions. Results reinforce the importance of mental health among patients hospitalized for AMI.
Abstract 11512: Association Between Use of Oral Anticoagulants After Minor Bleeding and Mortality Outcomes in Patients With Atrial Fibrillation: The Fushimi AF Registry
Authors: Kenjiro Ishigami, Hisashi Ogawa, Yumiko Nakanishi, Kimihito Minami, Syuhei Ikeda, KOSUKE DOI, Takashi Yoshizawa, Yasuhiro Hamatani, Yuya Ide, Akiko Fujino, Mitsuru Ishii, Moritake Iguchi, Nobutoyo Masunaga, Masahiro Esato, Hiromichi Wada, Koji Hasegawa, Mitsuru Abe, Masaharu Akao
Journal: Circulation (2022)

Introduction: Oral anticoagulants (OAC) reduce the risk of ischemic stroke, but may increase the risk of major or minor bleeding in atrial fibrillation (AF) patients. However, little is known about the management of anticoagulation in patients with AF after a minor bleeding event. This study assessed the association between use of OAC and outcomes in AF patients after minor bleeding. Methods: The Fushimi AF Registry is a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto, Japan. A total cohort of 4,489 AF patients were analyzed in the present study. We investigated patients in whom minor bleeding occurred during follow-up period, and compared between patients with OAC and those without OAC after minor bleeding. Results: During the median follow-up period of 1,844 days, minor bleeding occurred in 744 patients (5.7% per patient-year). After excluding patients with missing prescription data after minor bleeding, 494 patients were prescribed OAC and 234 were not prescribed after minor bleeding. Patients with OAC were more often non-paroxysmal type of AF (27.4% vs 48.0%, p&lt;0.01), and were more likely to have previous thromboembolism (23.3% vs 11.5%, p&lt;0.01) and heart failure (29.4% vs 19.2%, p&lt;0.01). They had significantly higher CHADS2 score (2.11 vs 1.79, p&lt;0.01). They were less likely to have history of major bleeding (2.6% vs 5.6%, p&lt;0.05). All-cause mortality after minor bleeding occurred in 91 patients with OAC (4.5% per patient-year) and 62 (7.5% per patient-year) patients without OAC with hazard ratio (HR) 0.62 (95% confidence interval [CI], 0.45-0.86; p&lt;0.01). After adjusted by age, sex, type of AF, and comorbidities, patients with OAC after minor bleeding were significantly associated with lower incidence of all-cause mortality (HR 0.52 [95% CI, 0.37-0.73; p&lt;0.01]). Conclusions: Conclusion: Use of OAC after minor bleeding was significantly associated with lower incidence of all-cause mortality in Japanese AF patients.
Abstract 11062: Temporal Change of Severity of Atrial Functional Mitral Regurgitation
Authors: Hiroko Hasegawa, Shunsuke Kagawa, Ken Kuwajima, Takafumi Yamane, Takahiro Shiota
Journal: Circulation (2022)

Introduction: Left atrial (LA) remodeling due to long burden of atrial fibrillation can cause atrial functional mitral regurgitation (A-FMR). However, longitudinal echocardiographic follow-up of patients with A-FMR has rarely been reported. Methods: We retrospectively identified 23 outpatients diagnosed with significant (≥ moderate) A-FMR on transthoracic echocardiography (TTE), with at least two studies performed more than one year apart. A-FMR was defined as 1) left ventricular ejection fraction ≥ 50% without regional wall motion abnormalities; 2) absence of primary valvular pathology; and 3) presence of atrial fibrillation. We excluded patients with significant aortic valve disease or mitral stenosis, treated valvular or congenital disease, any form of cardiomyopathy or carditis, or previous heart transplant. Follow-up was censored at the time of any interventions for valvular disease. The mitral regurgitation (MR) severity was graded based on the current guidelines, and classified as none (0); mild (1+); moderate (2+); moderate-to-severe (3+); or severe (4+). The change (Δ) of the echocardiographic variables between baseline and latest follow-up was assessed. Results: The median observation period was 3.4 [interquartile range: 2.6-6.6] years. At baseline, the mean LA diameter was 51 ± 7 mm and MR vena contracta width was 4.4 ± 1.1 mm. As shown in Figure 1a, 1b , there was a moderate positive correlation between observation period and Δ LA diameter (r = 0.504, P = 0.014). However, there was no significant correlation between observation period and Δ MR vena contracta width (r = -0.041, P = 0.85). During the observation period, guideline-based MR severity progressed in 4 (17%), unchanged in 12 (52%), and decreased in 7 (30%). The MR severity was not significantly different between baseline and follow-up (P = 0.60) ( Figure 1c ). Conclusion: In patients with A-FMR, LA size increased over time, whereas the severity of A-FMR did not progress significantly over time.